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Introduction
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September 2009 - present
Publications
Publications (41)
Nanoparticle biodistribution in vivo is an essential component to the success of nanoparticle-based drug delivery systems. Previous studies with fluorescently labeled expansile nanoparticles, or "eNPs", demonstrated a high specificity of eNPs to tumors that is achieved through a materials-based targeting strategy. However, fluorescent labeling tech...
Electrospun nanofibers are a 3D scaffold of choice for many drug delivery devices due to their high surface area, significant capacity for drug payload, ease of in situ placement, and scalable manufacture. Herein, we report the synthesis of polymeric, pH-responsive nanofiber buttresses via electrospinning. The homopolymer is comprised of an acrylic...
Risk of locoregional recurrence after sarcoma resection is high, increasing both morbidity and mortality. Intraoperative implantation of paclitaxel (PTX)-eluting polymer films locally delivers sustained, supratherapeutic PTX concentrations to the tumor bed that are not clinically feasible with systemic therapy, thereby reducing recurrence and impro...
Fas ligand (FasL), expressed on the surface of activated cytotoxic T lymphocytes (CTLs), is the physiological ligand for the cell surface death receptor, Fas. The Fas-FasL engagement initiates diverse signaling pathways, including the extrinsic cell death signaling pathway, which is one of the effector mechanisms that CTLs use to kill tumor cells....
The role of glucose-6-phosphate dehydrogenase (G6PD) in human cancer is incompletely understood. In a metabolite screening, we observed that inhibition of H3K9 methylation suppressed aerobic glycolysis and enhances the PPP in human mesothelioma cells. Genome-wide screening identified G6PD as an H3K9me3 target gene whose expression is correlated wit...
Background
Granzyme B is a key effector of cytotoxic T lymphocytes (CTLs), and its expression level positively correlates with the response of patients with mesothelioma to immune checkpoint inhibitor immunotherapy. Whether metabolic pathways regulate Gzmb expression in CTLs is incompletely understood.
Methods
A tumor-specific CTL and tumor cocult...
We describe the synthesis of poly(glycidyl acetate-co-glycidyl butyrate carbonate)s via the terpolymerization of glycidyl acetate (GA), glycidyl butyrate (GB), and CO2 by a cobalt salen complex in high atom economy. These new non-cytotoxic polycarbonates are pressure-sensitive adhesives, and peel testing shows the adhesive strength ranges from Scot...
Currently, no dressings utilized in burn clinics provide adhesion, hydration or mechanical strength on the same order as human skin as well as the ability to be atraumatically removed. We report the synthesis, characterization, and in vivo evaluation of in situ polymerized and subsequent dissolvable hydrogels as burn wound dressings. Hydrogel dress...
One of the foremost challenges in translating nanoparticle technologies to the clinic is the requirement to produce materials on a large-scale. Scaling nanoparticle production methods is often non-trivial, and the success of these endeavors is frequently governed by whether or not an intermediate level of production, i.e., “pilot-scale” production,...
Myeloid-derived suppressor cells (MDSCs) are immune suppressive cells that massively accumulate under pathological conditions to suppress T cell immune response. Dysregulated cell death contributes to MDSC accumulation, but the molecular mechanism underlying this cell death dysregulation is not fully understood. In this study, we report that neutra...
Lung cancer is the leading cause of cancer deaths worldwide. Unfortunately, high recurrence rates and poor survival remain despite surgical resection and conventional chemotherapy. Local drug delivery systems are a promising intervention for lung cancer treatment with the potential for improved efficacy with reduced systemic toxicity. Here, we desc...
Despite the presence of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment, the majority of immunogenic human colon cancers do not respond to immune checkpoint inhibitor immunotherapy and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unkno...
Objective:
Malignant pleural mesothelioma is a lethal malignancy with poor survival and high local recurrence rates despite multimodal therapy with cytoreduction and chemoradiation. We evaluated the antitumor efficacy of a paclitaxel-loaded pH-responsive expansile nanoparticle (PTX-eNP) in 2 clinically relevant murine xenograft models of malignant...
High-grade serous ovarian cancer (HGSOC) is the most lethal gynecological malignancy in women worldwide and the fifth most common cause of cancer-related deaths among U.S. women. New therapies are needed to treat HGSOC, particularly because most patients develop resistance to current first-line therapies. Many natural product and fungal metabolites...
Cover paper for CIR March Issue
Despite the presence of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment, the majority of immunogenic human colon cancer does not respond to immune checkpoint inhibitor immunotherapy, and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unk...
Six fungal metabolites, of which five were new, including one (1) with a dioxa[4.3.3]propellane ring system, were discovered, identified, and structurally elucidated from Neosetophoma sp. (strain MSX50044); these compounds are similar to the bis-tropolone, eupenifeldin. Three of the meroterpenoids are potent cytotoxic agents against breast, ovarian...
Despite the presence of CTLs in the tumor microenvironment, the majority of immunogenic human colon cancer does not respond to immune checkpoint inhibitor immunotherapy, and microsatellite instable (MSI) tumors are not naturally eliminated. The molecular mechanism underlying the inactivity of tumor-infiltrating CTLs is unknown. We report here that...
Chronic exposure of pancreatic β cells to high concentrations of free fatty acids leads to lipotoxicity (LT)‐mediated suppression of glucose‐stimulated insulin secretion. This effect is in part caused by a decline in mitochondrial function as well as by a reduction in lysosomal acidification. Because both mitochondria and lysosomes can alter one an...
This review presents an integrated analysis of the current-state-of-the-art in nucleic acid nanotherapies and highlights the importance of nanotechnology in the delivery of nucleic acid therapies. While there is no one dominant nanodesign, the diversity of nanodesigns and delivery of different siRNAs, miRNA and DNA to inhibit more than 20 targets i...
Human colon cancer, except for the small subset of microsatellite instable (MSI) colon cancer, does not respond to anti-PD-L1/PD-1 immune checkpoint inhibitor (ICI) immunotherapy. A well-established notion is that MSI colon cancer harbors various mutations that serve as neoantigens to generate tumor-specific cytotoxic T lymphocytes (CTLs). Because...
Background:
Pancreas ductal adenocarcinoma (PDAC) has the most dismal prognosis among all human cancers since it is highly resistant to chemotherapy, radiotherapy and immunotherapy. The anticipated consequence of all therapies is induction of tumor apoptosis. The highly resistance nature of PDACs to all therapies suggests that the intrinsic tumor...
The cover image, by Aaron H. Colby et al., is based on the Advanced Review Nanoparticle drug‐delivery systems for peritoneal cancers: a case study of the design, characterization and development of the expansile nanoparticle, DOI: 10.1002/wnan.1451.
Nanoparticle ( NP )‐based drug‐delivery systems are frequently employed to improve the intravenous administration of chemotherapy; however, few reports explore their application as an intraperitoneal therapy. We developed a pH ‐responsive expansile nanoparticle ( eNP ) specifically designed to leverage the intraperitoneal route of administration to...
A current challenge in the treatment of peritoneal carcinomatosis is the inability to detect, visualize, and resect small or microscopic tumors of pancreatic, ovarian or mesothelial origin. In these diseases, the completeness of primary tumor resection is directly correlated with patient survival, and, hence, identifying small sub-mm tumors (i.e.,...
Experimental studies of pH-responsive expansile nanoparticles (eNPs) have been carried out using tunable resistive pulse sensing (TRPS) and nanoindentation. The eNPs are initially ∼200 nm in diameter, but increase in size owing to a compositional change resulting from cleavage of pH-labile protecting groups on the polymer backbone at low pH. TRPS d...
Experimental studies of pH-responsive expansile nanoparticles (eNPs) have been carried out using tunable resistive pulse sensing (TRPS) and nanoindentation. The eNPs are initially ∼200 nm in diameter, but increase in size owing to a compositional change resulting from cleavage of pH-labile protecting groups on the polymer backbone at low pH. TRPS d...
In pancreatic β-cells, liver hepatocytes, and cardiomyocytes, chronic exposure to high levels of fatty acids (lipotoxicity) inhibits autophagic flux and concomitantly decreases lysosomal acidity. Whether impaired lysosomal acidification is causally inhibiting autophagic flux and cellular functions could not, up to the present, be determined because...
The treatment outcomes for malignant peritoneal mesothelioma are poor and associated with high co-morbidities due to suboptimal drug delivery. Thus, there is an unmet need for new approaches that concentrate drug at the tumor for a prolonged period of time yielding enhanced antitumor efficacy and improved metrics of treatment success. A paclitaxel-...
Aim:
To evaluate the tumor localization and efficacy pH-responsive expansile nanoparticles (eNPs) as a drug delivery system for pancreatic peritoneal carcinomatosis (PPC) modeled in nude rats.
Methods & materials:
A Panc-1-cancer stem cell xeno1graft model of PPC was validated in vitro and in vivo. Tumor localization was tracked via in situ imag...
Drug dose, high local target tissue concentration, and prolonged duration of exposure are essential criteria in achieving optimal drug performance. However, systemically delivered drugs often fail to effectively address these factors with only fractions of the injected dose reaching the target tissue. This is especially evident in the treatment of...
The size, drug loading, drug release kinetics, localization, biodistribution, and stability of a given polymeric nanoparticle (NP) system depend on the composition of the NP core as well as its surface properties. In this study, novel, pH-responsive, and lipid-coated NPs, which expand in size from a diameter of approximately 100 nm to 1000 nm in th...
Objectives:
Intraperitoneal administration of paclitaxel-loaded expansile nanoparticles (Pax-eNPs) significantly improves survival in an in vivo model of malignant mesothelioma compared with conventional drug delivery with the clinically utilized Cremophor EL/ethanol (C/E) excipient. However, in vitro monolayer cell culture experiments do not repl...
Through a series of in vitro studies, the essential steps for intracellular drug delivery of paclitaxel using a pH-responsive nanoparticle system have been investigated in breast cancer cells. We successfully encapsulated paclitaxel within polymeric expansile nanoparticles (Pax-eNPs) at 5% loading via a miniemulsion polymerization procedure. Fluore...
Polymeric expansile nanoparticles (eNPs) that respond to a mildly acidic environment by swelling with water and expanding 2-10× in diameter represent a new responsive drug delivery system. Here, we use a variety of techniques to characterize the pH- and time-dependence of eNP swelling as this is a key property responsible for the observed in vitro...
Scanning ion occlusion sensing (SIOS), a technique that uses a tunable pore to detect the passage of individual nano-scale objects, is applied here for the rapid, accurate and direct measurement of synthetic and biological nanoparticle concentrations. SIOS is able to characterize smaller particles than other direct count techniques such as flow cyt...